Longitudinal evaluation of the impact of immunosuppressive regimen on immune responses to COVID-19 vaccination in kidney transplant recipients

Abstract

Immunocompromised patients have a high risk of death from SARS-CoV-2 infection. Vaccination with an mRNA vaccine may protect these patients against severe COVID-19. Several studies have evaluated the impact of immune-suppressive drug regimens on cellular and humoral responses to SARS-CoV-2 variants of concern in this context. We performed a prospective longitudinal study assessing specific humoral (binding and neutralizing antibodies against spike (S) and T-lymphocyte (cytokine secretion and polyfunctionality) immune responses to anti-COVID-19 vaccination with at least two doses of BNT162b2 mRNA vaccine in stable kidney transplant recipients (KTR) on calcineurin inhibitor (CNI)- or belatacept-based treatment regimens. Fifty-two KTR-31 receiving CNI and 21 receiving belatacept-were enrolled in this study. After two doses of vaccine, 46.9% of patients developed anti-S IgG. Anti-spike IgG antibodies were produced in only 21.4% of the patients in the belatacept group, vs. 83.3% of those in the CNI group. The Beta and Delta variants and, more importantly, the Omicron variant, were less well neutralized than the Wuhan strain. T-cell functions were also much weaker in the belatacept group than in the CNI group. Renal transplant patients have an impaired humoral response to BNT162b2 vaccination. Belatacept-based regimens severely weaken both humoral and cellular vaccine responses. Clinically, careful evaluations of at least binding IgG responses, and prophylactic or post-exposure strategies are strongly recommended for transplant recipients on belatacept-based regimens.

Keywords: COVID-19; immune responses; immunocompromised; immunosuppressive regimen; mRNA vaccine.

Figure 1

Antibody responses induced by vaccination with the BNT162b2 mRNA vaccine in patients treated with calcineurin inhibitor (CNI) or belatacept. SARS-CoV-2-specific IgG binding antibody responses directed against the native trimeric S protein at baseline (pre-vacc), 21 days after the first dose (post-dose 1), 14 days after the second dose (post-dose 2), and at M3 and M6 post-vaccination in patients treated with CNI (n = 18) (circles)or belatacept (n = 14) (triangles). Blue squares indicate patients who received the 3rd (booster) dose of vaccine at least 10 days before the follow-up visit. The dashed red line indicates the positivity threshold (12 U/ml). Median values ± IQR are shown. Mann-Whitney tests and, Friedman and Dunn's multiple comparison tests were used for statistical analysis. Statistical p value are indicated as followed (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001).

Figure 2

Neutralizing activity against spike protein mutations associated with VOCs, 14 days after the second dose (post-dose 2), and at M3 and M6 post-vaccination, in transplanted patients. Frequency of patients with nAb responses directed against the original strain and the various VOCs. A negative result (gray bars) indicates an IC₅₀ titers < 50 dilutions; a positive result (colored bars) indicates an IC₅₀ titers > 50 dilutions (A). Neutralizing antibody responses were assessed by determining the half maximal inhibitory concentration (IC₅₀) dilutions. The dotted red line indicates the threshold for assay positivity (i.e., IC₅₀ > 50 dilutions). Data are expressed as IC₅₀ (half maximal inhibitory concentration) dilutions (B).

Figure 3

Spike-specific T-cell responses induced by vaccination with BNT162b2 in patients treated with calcineurin inhibitor (CNI) or belatacept. S-specific CD4 and CD8 T-cell responses in patients treated with CNI (n = 24) (A) or belatacept (n = 17) (B), after overnight stimulation with a pool of overlapping peptides covering the wild-type Spike protein at baseline (pre-vacc), 21 days after the first dose (post-dose 1), 14 days after the second dose (post-dose 2), and at M3 and M6 post-vaccination. Blue squares indicate patients who received a 3rd (booster) dose of vaccine at least 10 days before the follow-up visit. Functional composition of S-specific CD4 T-cell responses in vaccinated patients treated with CNI. Responses are color-coded according to the combination of cytokines produced. The arcs identify cytokine-producing subsets (IFN-γ, IL-2, and TNF) within the CD4 T-cell population (C). Kruskal-Wallis and Dunn's multiple comparison tests were used for statistical analysis (*P < 0.05, **P < 0.01, ***P < 0.001).